Fasudil 预处理可通过减少活性氧的积累来防止新霉素引起的毛细胞损伤。,Frontiers in Molecular Neuroscience

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Fasudil 预处理可通过减少活性氧的积累来防止新霉素引起的毛细胞损伤。
Frontiers in Molecular Neuroscience ( IF 3.5 ) Pub Date : 2019-11-06 , DOI: 10.3389/fnmol.2019.00264
Yanqiu Zhang _{1,

2,

3,

4} , Wei Li _{1,

2,

3,

5} , Zuhong He _{2,

6} , Yunfeng Wang _{7,

8} , Buwei Shao ₂ , Cheng Cheng _{1,

2,

3} , Shasha Zhang ₂ , Mingliang Tang ₂ , Xiaoyun Qian ₁ , Weijia Kong ₆ , Hui Wang ₉ , Renjie Chai _{2,

3,

7,

10,

11,

12} , Xia Gao _{1,

3}

Affiliation

Jiangsu Provincial Key Medical Discipline (Laboratory), Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
MOE Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.
Research Institute of Otolaryngology, Nanjing, China.
Department of Otolaryngology Head and Neck Surgery, Xuzhou Cancer Hospital, Xuzhou, China.
Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Hearing Medicine of NHFPC, State Key Laboratory of Medical Neurobiology, ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Shanghai Engineering Research Centre of Cochlear Implant, Fudan University, Shanghai, China.
Shanghai Fenyang Vision & Audition Center, Shanghai, China.
Department of Otolaryngology Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.
Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.

耳毒性药物引起的毛细胞（HC）损伤是感音神经性听力损失的主要原因之一，感音神经性听力损失是人类最常见的感觉障碍之一。氨基糖苷类抗生素是常见的耳毒性药物，可引起细胞内氧自由基的积累并导致HC细胞凋亡。法舒地尔是一种Rho激酶抑制剂和血管扩张剂，已广泛应用于临床，并已被证明具有神经保护作用。然而，法舒地尔在预防氨基糖苷类引起的 HC 损失和听力损失方面的可能应用尚未得到研究。在这项研究中，我们研究了法舒地尔在体外和体内防止新霉素诱导的 HC 损失的能力。我们发现，法舒地尔显着减少了耳蜗全器官外植体培养物中的 HC 损失，并减少了体外暴露于新霉素后听觉 HEI-OC1 细胞的细胞死亡。此外，我们发现法舒地尔在体内新霉素损伤模型中显着预防小鼠的HC损失和听力损失。此外，我们发现在新霉素暴露后，法舒地尔能够显着抑制听觉HEI-OC1细胞中的Rho信号通路，从而进一步减少新霉素诱导的活性氧积累和随后的HEI-OC1细胞凋亡。这项研究表明，法舒地尔可能通过抑制 Rho 信号通路来增加接触新霉素后 HC 的活力，并提出了预防氨基糖苷类药物引起的 HC 损失和听力损失的新治疗靶点。

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Pre-treatment With Fasudil Prevents Neomycin-Induced Hair Cell Damage by Reducing the Accumulation of Reactive Oxygen Species.

Ototoxic drug-induced hair cell (HC) damage is one of the main causes of sensorineural hearing loss, which is one of the most common sensory disorders in humans. Aminoglycoside antibiotics are common ototoxic drugs, and these can cause the accumulation of intracellular oxygen free radicals and lead to apoptosis in HCs. Fasudil is a Rho kinase inhibitor and vasodilator that has been widely used in the clinic and has been shown to have neuroprotective effects. However, the possible application of fasudil in protecting against aminoglycoside-induced HC loss and hearing loss has not been investigated. In this study, we investigated the ability of fasudil to protect against neomycin-induced HC loss both in vitro and in vivo. We found that fasudil significantly reduced the HC loss in cochlear whole-organ explant cultures and reduced the cell death of auditory HEI-OC1 cells after neomycin exposure in vitro. Moreover, we found that fasudil significantly prevented the HC loss and hearing loss of mice in the in vivo neomycin damage model. Furthermore, we found that fasudil could significantly inhibit the Rho signaling pathway in the auditory HEI-OC1 cells after neomycin exposure, thus further reducing the neomycin-induced accumulation of reactive oxygen species and subsequent apoptosis in HEI-OC1 cells. This study suggests that fasudil might contribute to the increased viability of HCs after neomycin exposure by inhibition of the Rho signaling pathway and suggests a new therapeutic target for the prevention of aminoglycoside-induced HC loss and hearing loss.

更新日期：2019-11-01

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